Unlike alpha/beta T cells, gamma/delta T cells preferentially reside in epithelial tissues covering the external and internal surface of a body, where they function in the first line of defense, such as regulation of inflammation, tumor surveillance and tissue repairing. Using transgenic and knockout mouse models as experimental approaches, we will try to uncover molecular mechanisms underlying development and specific tissue distribution of gamma/delta T cells in the skin. Nearly all skin gamma/delta T cells express identical Vgamma3/Vdelta1 T cell receptors and originate from the fetal thymus. Positive selection of gamma/delta T cells in the fetal thymus is associated with a coordinate switch in expression of a set of chemokine receptors potentially important for their peripheral tissue distribution in the skin. To further understand this process, I propose to dissect the TCR/ligand interaction-mediated fetal thymic selection process of gamma/delta T cells, in relationship with their unique homing properties and skin-specific tissue distribution and determine the positive selection associated CCR10 upregulation and CCR6 downregulation in sIEL development. These studies will help understand how immune cells go to different local tissues where they are positioned to fight against infection and tumor growth. This knowledge will be useful in helping to find a way to direct immune cells to specific tissues to treat different diseases. PUBLIC HEALTH RELEVANCE: Tissue specific lymphocytes are important components of immune system and play an important role in the first line of defense against diseases. I propose here to study developmental mechanism of a class of skin-specific lymphocyte populations. These studies will help understand how immune cells go to different local tissues where they are positioned to fight against various diseases.